Download Undergraduate/Graduate Category: Physical and Life Sciences Degree Level: Candidate for Bachelor’s Degree

Undergraduate/Graduate
Category: Physical and Life Sciences
Degree Level: Candidate for Bachelor’s Degree
Abstract ID# 1069
Pre-clinical Pilot Study of a Light Activated Doxorubicin Derivative
Sarah Sherman1, Alana Ross2, Chongzhao Ran2, Byunghee Yoo2, Pamela Pantazopoulos2, Ping Wang2, Benjamin L. Barthel3, Tad H. Koch3, Anna Moore2
1 Dept.
of Biology, Northeastern University; 2 Molecular Imaging Laboratory, Department of Radiology, Massachusetts General Hospital/Harvard Medical School; 3Department of Chemistry and
Biochemistry, University of Colorado
Preliminary assessment of drug toxicity
Abstract
2 weeks
40 minutes
Mouse Weight
Therapy
starts with ip
injection of
18F-FDG.
(350-500 μCi)
Female nude
mice injected
with MDA MB
231 luc cells
(n=13)
Caged Dox
given by iv
injection.
Therapy and
imaging
continues
weekly.
Results
Experimental Groups
Treatment: FDG + Caged
Dox
Control 1: FDG + Vehicle
Control 2: Doxorubicin
n
5
Drug Dose (mg/mouse)
0.1
4
4
0.1
0.1
24
23
20
Figure 1: Cherenkov luminescence (left) and PET (right) images of
a mouse from a treatment group on the first day of treatment.
These images depict tumor uptake of 18F-FDG, which produces the
Cherenkov radiation that activates caged Dox. The Cherenkov
luminescence imaging allows for direct confirmation of the
presence of this radiation.
Tracking Tumor Size
11/13/15
Treatment
10/23/2015
Vehicle control
Dox control
Experimental Design
25
21
Demonstrating Tumor Uptake of 18F-FDG
Approach
Challenge: Light can’t travel far through tissues
Solution: Use 18F-FDG, which produces Cherenkov
radiation, as a light source that can be localized to the
tumor
26
0
10/5/2015
Solving the Depth Problem-Cherenkov Radiation
27
22
Introduction
Doxorubicin (Dox) is an FDA approved chemotherapeutic used to
treat a variety of cancers. However, its potential to damage the
heart and other vital organs limits the amount patients can
receive. This study examines the performance of a potent, caged
derivative of doxorubicin which is inactive until exposed to light.
This mechanism of selective activation will result in more efficient
treatment and reduced systemic toxicity.
28
Weight (g)
This study examines the effects of a caged, potent derivative of
doxorubicin that is activated by light in a preclinical model of
orthotopic breast cancer. This mechanism of activation allows caged
Dox to be selectively released at the site of the tumor, resulting in
decreased systemic toxicity and greater treatment efficiency. Mice
were injected with MDA MB 231 luc cells and sorted into treatment,
vehicle control, and doxorubicin only control groups. Treatment and
bioluminescence imaging to monitor tumor size were carried out
weekly. Weights were collected twice a week. There was no significant
change in tumor radiance in the treatment group (t =.416). However,
mice in the doxorubicin control group lost a significant amount of
weight, (t=.042) while the treatment group did not (t=.377). This
indicates that caged Dox is potentially less toxic than doxorubicin.
Further studies are necessary to address problems with the drug’s
efficacy, which may be due to poor pharmacokinetics or a need to
optimize dose timings in the treatment protocol.
10
Treatment
20
30
40
50
Days Post
Initial TreatmentDox Control
Vehicle Control
Figure 3: Average weights of the treatment and two control
groups over time. The doxorubicin group experienced a significant
weight loss over the course of the experiment. (p<.0001) No
significant weight loss occurred in the treatment group.
(p=0.0992). No significant change in weight occurred in the control
group up until the last time point all mice were alive. (p=0.8996)
The stability of the treatment group’s weight indicates the
possibility that caged Dox may be less toxic than doxorubicin.
Conclusions
• Preliminary results show caged Dox may be less toxic than
doxorubicin. Verification with H&E staining of tissues is
needed.
• Issues with pharmacokinetics, radiation dosing, or timing of
treatment may be interfering with drug efficacy. Further studies
could look at optimization of dosing and the time gap between
administration of 18F-FDG and caged Dox.
• A second generation of this drug is under development, with a
focus on improving solubility and tumor targeting.
Bibliography
X.1
Figure 2: Bioluminescence images of mice with orthotopic breast
tumors, n=3. The image parameters for min. and max. radiance are
standardized within a group. The x.1 indicates that the parameters
for this image have been lowered by a factor of ten. There was no
significant change in the treatment group’s average signal
throughout the experiment. (p= 0.6316)
[1] Ran C, Zhang Z, Hooker J, Moore A. In Vivo Photoactiviation Without “Light”: Use of Cherenkov Radiation
to Overcome the Penetration Limit of Light. Mol. Imaging and Biology 2012; 14: 156-162.
[2] Zhang X, Kuo C, Moore A, Ran C. In Vivo Optical Imaging of Interscapular Brown Adipose Tissue with 18FFDG via Cherenkov Luminescence Imaging. Plos One 2013; 8: e62007
[3] Barthel B, et al. Preclinical Efficacy of a Carboxylesterase 2-Activated Prodrug of Doxazolidine. Journal of
Medicinal Chemistry 2009; 52: 7678-7688
[4] Gibbs, Philip. 1997. Is there an equivalent of the sonic boom for light? [Internet]. [1998, cited 2015 Dec
13] . Available from:
http://math.ucr.edu/home/baez/physics/Relativity/SpeedOfLight/cherenkov.html
[5] Cherenkov effect in the Reed Research Reactor. United States Nuclear Regulatory Comission [Internet]
[cited Dec 13 2015]. Available from http://www.nrc.gov/images/reading-rm/photo-gallery/20071115067.jpg.